Postgrad Med J: first published as 10.1136/pgmj.48.564.594 on 1 October 1972. Downloaded from

Postgraduate Medical Journal (October 1972) 48, 594-598.

The treatment of chronic pain with psychotropic H. MERSKEY R. A. HESTER* D.M., M.R.C.Psych., D.P.M. M.B., B.S., D.P.M. The National Hospitals for Nervous Diseases, Queen Square and Maida Vale, London Summary of , and were of little help The treatment is described of thirty patients with for pain which was mainly due to psychological ill- chronic nervous system lesions causing intractable ness. On the other hand, Lance & Curran (1964) pain. Moderately good relief of pain was obtained recorded the view that could have an with a combination of phenothiazines (especially effect which was independent of its anti- pericyazine), drugs and . action, although this claim was criticized The theoretical implications of this are discussed severely by Holt (1964) on statistical grounds. and it is suggested that the drugs in question act partly A number of reports indicate that phenothiazines by virtue of an effect on the multisynaptic neuronal can play a part in the control of pain which has a systems whose activities are related to the experience definite organic basis. Sigwald, Hebert & Quetin of pain. (1957) described the successful treatment of resistant forms of pain with which is both a A WIDE range of psychological circumstances will and an . They obtained cause, exacerbate or relieve pain. frequently still better results with . Sigwald,

produces pain or makes it worse, whilst the reduc- Boutier & Caille (1959) reported yet more effectby copyright. tion of anxiety by drugs, psychotherapy and plain from . Lasagna & De Kornfeld suggestion may alleviate pain. The evidence for this (1961) showed that methotrimeprazine was as effec- view-which is generally agreed- has been reviewed tive as when given for postoperative pain. elsewhere (Merskey & Spear, 1967). Other reports recording the use of phenothiazines Anaesthetists are very active in studying the tech- for chronic pain were provided by Panaccio (1959), niques of discussion and support which will relieve Chavanne (1960) and Paradis (1962). Montilla, postoperative pain. For example Egbert et al. (1964) Frederik & Cass (1963) also demonstrated analgesic showed that in patients who were given suitable pre- effects of phenothiazines. hydro- operative encouragement smaller doses of analgesic chloride, an antihistamine has been reported to drugs were required postoperatively than by a con- markedly potentiate the effects of novocaine (Ros- trol group. It is worth noting however, that, as a ner, 1957). Doctors engaged in the treatment of pain http://pmj.bmj.com/ rule, pain tends to be reduced rather than abolished from neoplasms also recognize an analgesic effect by psychological techniques. The complete removal of tranquillizers, although they tend to attribute it of severe pain often requires potent drugs. whollyormainlytotheabatingoffear(Saunders, 1963; Although many are known there is Bloomfield et al., 1964; Saunders & Winner, 1971). sometimes a mistaken impression that, if paraceta- Even with chronic pain from non-progressive mol and fail, the patient with chronic lesions, for instance in the thalamic syndrome, there pain due to an organic lesion faces the alternatives is evidence that phenothiazines may be strikingly of depending on more or less dangerous drugs or beneficial, without the patient having shown notable on October 2, 2021 by guest. Protected undergoing a neurosurgical operation with some- evidence of anxiety (cf. for example, the report by times considerable risks. It is of course well recog- Lassmann, Moody & Gryspeerdt, 1959). nized that certain pain-syndromes, especially head- These reports indicate that a fairly sustained use of ache and facial pain may yield to antidepressant psychotropic drugs like and medication. Lascelles (1966) showed this in a con- phenothiazines, with, perhaps, antihistamines, could trolled trial. There is an impression, however, that be helpful in the management of chronic pain. It is those patients improve who show depression-and an open question as to whether their effect takes perhaps it was the depression that produced the place solely because anxiety is reduced or partly pain. Certainly one of us (Merskey, 1965) found that because they have some additional analgesic quali- antidepressants only helped psychiatric patients with ties. Since other powerful agents like pain where there was an affective illness which could are not usually effective for severe ordinarily be expected to respond to the treatment chronic pain it is reasonable to suppose that the * Present address: Netherne Hospital, Coulsdon, Surrey. analgesia is not only due to the reduction of anxiety. Postgrad Med J: first published as 10.1136/pgmj.48.564.594 on 1 October 1972. Downloaded from

Treatment ofpain with psychotropic drugs 595

One of us (H.M.) sees numerous patients who are few complaints when elated. In at least two of the referred for treatment of pain, whether or not this is patients with a thalamic syndrome it was hard to attributable to psychological causes. Many, in fact, be sure, however, whether the depression and pain have pain due primarily to organic lesions, almost did not originate simultaneously from the brain all of which affect the nervous system and are not damage and one in fact responded well to ECT, progressive. In treating this latter group we have being the only one to whom it was given. come to rely quite heavily on various sorts of non- Treatment was inevitably complex. Some patients narcotic medication. We think it may be useful to had physiotherapy (e.g. for cervical spondylosis) and others to describe the practice employed and some the use of a vibrator, and drugs of the following of its results. The treatment situation is such that types were used in varying combinations: controls or systematic study of the effects of each (1) Narcotic analgesics in four of the seven who alone is not feasible. Yet our methods appear had originally received them, albeit in reduced doses to be helpful to people for whom surgery may be the in two instances. only alternative. We therefore offer an account of (2) Non-narcotic analgesics, especially pentazo- thirty patients with whom we have used mixtures of cine, and and the psychotropic drugs, and their response to this proprietary combination of the latter two (Distal- medication. gesic). (3) Antidepressants. Patients and treatments (4) Phenothiazines. The patients concerned are eleven men and nine- (5) Antihistamines, especially promethazine. teen women selected for the presence of severe persistent pain related to an organic lesion. Their Results median ages are-males, 58 years; females, 56 years. The median period of follow-up was 6 months. Seven patients were single or widowed. The median Using two or more of the possible combinations of duration of illness was 5 years for men and 4 years these drugs substantial relief was provided for by copyright. for women, with an overall range of from 6 months twelve patients, moderate relief for nine and slight to 25 years of pain. The diagnoses were: post- relief for seven. No improvement occurred in two. herpetic neuralgia (seven patients), thalamic syn- Ideally it would have been desirable to have used drome (six patients), facial pain (six women and one each type of drug separately so as to evaluate the man), causalgia (five patients), phantom pain (one effects in comparison with other types. The attempt patient), Plget's disease ofthe leg bones (one patient), was made, in part, to do this, but with limited suc- cervical spondylosis (one patient), and carcinoma cess, since it is hard and probably wrong to postpone (two patients). the use of potentially effective treatments for people Nine patients had undergone operative procedures in considerable distress so long as the treatments are for their pain, sometimes repeatedly and seven reasonably safe. more were receiving narcotic analgesics (including Moreover, it was already known that antidepres- http://pmj.bmj.com/ the two patients with neoplasms). Two patients had sants and analgesics had failed to help a number of had ECT and seven had had antidepressants. Five patients. Accordingly all the patients considered had of the latter seven had also had phenothiazines, as further combinations of drugs. had one other patient. had also been The most successful single type appeared to be tried in six cases. Many patients had lost count of the phenothiazines since all the twelve best results their drug treatments and analgesic tablets taken so occurred with them. Ten of the twelve best results that the above represent minimum estimates. were also associated with antidepressants. Anti- Neurological data for these patients were readily were associated with five of the best on October 2, 2021 by guest. Protected available, often with useful information on the results, but the antihistamines used on their own for a patient's social circumstances and mood. The few days initially seemed ineffective. Antihistamines approach used was then to complete a psychiatric were valuable, however, for reasons to be mentioned, history, explaining that one of us (H.M.) was in supplementing night . particularly interested in the treatment of pain and The usual dosages of antidepressants were em- also in any personal problems or circumstances ployed. That of the favourite phenothiazine (peri- which might make the pain harder to- tolerate. All cyazine), was from as little as 5 0 mg daily to as much but one of the thirty patients showed evidence of as 225 0 mg daily, the higher dose ranges only being moderate depression. In all but one of the twenty- approached gradually. nine with depression it was thought that the depres- The pattern oftreatment which evolved was largely sion was secondary to the pain rather than primary. as follows: The exception was a woman with manic-depressive A patient, often already taking an antidepressant mood-swings and post-herpetic neuralgia who had would be given promethazine at night, and the dose Postgrad Med J: first published as 10.1136/pgmj.48.564.594 on 1 October 1972. Downloaded from

596 H. Merskey and R. A. Hester of the antidepressant increased if feasible to assist area and would not allow her children to kiss it. sleep. might also be used to promote She continued at work taking some 150 paracetamol sleep if required. After 3 or 4 days there was usually or Distalgesic tablets a week but was depressed and little improvement and pericyazine would be intro- had frequent suicidal thoughts. No physical abnor- duced once or twice a day with a larger dose at night, mality was detectable by physical examination or by gradually increasing until good sleep obtained and investigations including blood count, CSF examina- the patient tended to complain of a dry mouth and tion, EEG, brain scan or right carotid and vertebral drowsiness by day as well (pericyazine is a relatively angiograms. Nevertheless, the condition was thought phenothiazine). After two or three restful to have an organic basis and her depression to be nights the patients generally appeared better and secondary to the pain. Substantial and increasing said their pain was improved, in some instances relief appeared within 5 days with the use of amitrip- dramatically so. But reduction of the day-time dose tyline 75 mg nocte, pericyazine 10 mg t.d.s., 20 mg of pericyazine without a relapse of ordi- nocte, and 16 Distalgesic tablets daily. The pain was narily caused an exacerbation of the pain. A valuable only present then, on waking, for about an hour and distinct effect was also obtained by more until her first medication in the day began to take vigorous use of the non-narcotic drugs in addition. effect. Six weeks later she had reduced her total dose Thus, a patient taking say, two Distalgesic tablets of pericyazine to 25 mg nocte because the day-time three times a day and waiting for them until his pain dose made her too relaxed. She continued to use was quite severe would be given two or three such amitriptyline 75 mg nocte and if pain seemed to be tablets, five times daily, punctually at fixed times about to recur it was prevented by taking two such that the preceding doses had not had time to Distalgesic tablets at a time. There were feelings of wear off. There is an impression (Vitali, 1971; discomfort but no actual pain. Foster, 1971; Winner, 1971) which we share that it is very important once pain has been reduced or Comment abated to prevent its resurgence in this way. If it is Both amitriptyline and pericyazine were importantby copyright. allowed to return in full force it takes more than just first of all in securing good sleep. They appeared to one or two doses again to restore the benefit that reduce the overall level of pain so much that it has been lost. became possible to abolish it with only small doses The good effects of any of these combinations of of previously insufficient analgesics. In patients with drugs may also be lost by the administration of pain due solely to depression, analgesics are usually or of . The same applies to not necessary as a supplement to antidepressants. narcotic drugs. The first two and perhaps also the In addition the effect ofamitriptyline and pericyazine third reduce the potency of other medication by was so quick to appear that it is unlikely to have been virtue of their tendency to induce hepatic enzymes. related principally to an antidepressant effect. It is In this connection promethazine is useful with nitra- more likely to have been due to an analgesic effect of zepam for its effect as a mild , supplement- pericyazine, and perhaps a dual antidepressant and http://pmj.bmj.com/ ing the night-time doses of antidepressants and analgesic effect of amitriptyline. phenothiazines. The following case histories illus- trate the effect of the psychotropic drugs. Case 2 Case 2 is a married professional woman born in Case 1 1924, the bread-winner of her family with a much A married 50-year-old woman who presented in older invalid husband, and two sons aged 14 and 8 May 1971 with continuous severe right facial pain years, handicapped by congenital illness and in of over 3 year's duration. In January 1968 two upper receipt of private education. Her childhood was on October 2, 2021 by guest. Protected premolar teeth were extracted for toothache and unhappy and she was nervous and shook easily but the gums were stitched because of a tendency to served in the WAAF, was a sergeant during the war bleed. A month later she developed pain in the gums and was mentioned in despatches. Her marriage was at the site of extraction, not relieved by the sub- happy. In July 1964 she sustained a partial right sequent removal of the adjoining canine tooth. median nerve lesion which produced causalgia Over a period of about 6 months the pain became which persisted despite settlement of a legal claim more intense and spread so that for over 2j years in March 1970. Combined antidepressants in the she had continual deep aching pain affecting a form of trimiprazine at night, and phenalzine by day triangle of the right side of the face in an area and chlordiazepoxide produced only temporary marked out by the upper lip and gum, the nose, the improvement. She was first seen by us in December orbit, the temporo-mandibular joint and the tragus 1970 when she had severe pain, sometimes extending of the ear. There was also a tingling numbness 'like to the elbow and shoulder. She said it wore her out an exposed nerve' and she was gentle in washing the and she would have committed suicide were it not Postgrad Med J: first published as 10.1136/pgmj.48.564.594 on 1 October 1972. Downloaded from

Treatment ofpain with psychotropic drugs 597 for her children. She held her right hand slightly of causalgia was dose-dependent. The complications adducted and was tense and tearful. At the time of sustained indicate a potential use for tricyclic drugs referral she was having 150 mg nocte, and sometimes anti-parkinsonian ones in order to 15 mg t.d.s. and chlordiazepoxide 10 mg permit the continued employment of pericyazine in t.d.s. She was asked to continue these drugs adding a relatively high dose. promethazine 25'0 mg nocte. No improvement hav- The analgesic effect of pericyazine was apparently ing occurred after 1 week she was then told to add specific in this patient. pericyazine 5 mg mid-day and 10 mg nocte rising to 10 mg mid-day and 20 mg nocte. A further Side-effects and precautions increase of pericyazine to 25 mg b.d., 50 mg nocte This last case leads on to a consideration of the abolished her pain altogether within 3 weeks of side-effects from these not inconsiderable doses of starting treatment. drugs. Those of the antidepressants are well-known She remained well for 2 weeks when oedema of the and will not be reviewed. It is becoming increasingly legs developed, a complication sometimes noted with recognized that phenothiazines may cause depres- combined antidepressants and a phenothiazine, and sion and simultaneously, the most she was advised to reduce the pericyazine, which she notable evidence probably being that of de Alarcon did, whereupon pain recurred. She was therefore & Carney (1969). Our second patient described illus- asked to stop the phenelzine and restore the peri- trates how a reversible syndrome of parkinsonism cyazine. Within 2 days the pain was again abolished and depression emerged when the antidepressants and after 10 days the oedema resolved. were stopped and pericyazine continued. It seems Some drowsiness was noted with the pericyazine not unlikely that both these consequences were but she was able to continue with all her responsi- initially averted by her antidepressants. In this con- bilities and remained free of pain. nection the spontaneous occurrence of parkinsonism In February 1971 a programme was arranged to and depression together and their apparent response reduce drugs which might not be required and she to antidepressants and sometimes ECT is apposite. by copyright. dispensed successfully with promethazine and In the treatment of pain by phenothiazines it is chlordiazepoxide. The pericyazine was also reduced therefore probably wise to use antidepressants. to 87 5 mg daily. Then her trimipramine was also A troublesome side-effect which might be antici- gradually reduced to 50 mg nocte. pated with these combinations is postural hypo- In May 1971 she returned for an urgent consulta- tension but we have not had complaints of it in this tion because of severe depression which had de- series. veloped insidiously as her drugs were reduced. There Transient impairment of micturition is a problem was no pain but she was unable to cope with her sometimes making necessary reduction of the anti- work and she spent her time sitting around, lacking depressant. almost always occurs and energy. She was deluded that it was impossible to is usually manageable but we have had a patient help her, that she had spent extravagantly, that she (not in this series) who became so constipated that http://pmj.bmj.com/ could not afford the rail fare for her NHS appoint- his haemorrhoids prolapsed and he required a ments, and that she would not recover. Physically haemorrhoidectomy. The production of oedema is she had a mask-like facies, cogwheel rigidity in the also not confined to phenelzine or . limbs combined with and involuntary Tricyclic antidepressants and phenothiazines seem movements of the tongue at rest. Conjugate devia- to provoke water-retention at times and especially tion on upward gaze was lost. when in combination, although the patient described She was thought to have a drug-induced syndrome is the only one in this series who developed frank of parkinsonism and endogenous depression. She oedema. on October 2, 2021 by guest. Protected would only agree to reduce her pericyazine (where- It is worth remarking further that some patients, upon her pain recurred in part) and not to stop it. having gained control of their pain-or thinking The restoration of trimipramine 150 mg nocte and that the drugs do not help, attempt to stop their the use of 50 mg t.d.s. resolved her medication suddenly. In our experience their pain is depression and parkinsonism within 3 weeks (i.e. by usually severe after this and they then recognize the June 1971) and she has remained well since that time, help the medication was giving. But some deliber- taking 150 mg of trimipramine, 150 mg of orphen- ately cut their dose, knowing their pain will be worse, adrine and 100 mg of pericyazine, daily, the latter because their maximum benefit is accompanied by two drugs in divided doses. too much drowsiness and they feel the need to be able to concentrate better at work. Comment In this case repeated reductions of pericyazine Discussion were accompanied by a return of pain, and the relief We hope this account has shown that a combina- Postgrad Med J: first published as 10.1136/pgmj.48.564.594 on 1 October 1972. Downloaded from

598 H. Merskey and R. A. Hester tion ofpsychotropic drugs, especially antidepressants FOSTER, C.A. (1971) In: Proceedings of a Symposium on Pain in Disablement, p. 34. National Fund for Research into and phenothiazines, but possibly also antihistamines, Crippling Diseases, London. can be very useful in the control of chronic pain. It HOLT, N.F. (1964) Treatment of chronic tension headache. is evident that the combination is not a panacea and Lancet, ii, 1067. that it can also cause troublesome side-effects. Apart LANCE, J.W. & CURRAN, D.A. (1964) Treatment of chronic tension headache. Lancet, ii, 1236. from its therapeutic use the most interesting question LASAGNA, L. & DE KORNFELD, T.J. (1961) Methotrimepra- it raises is the relationship to the experience of pain. zine: A new phenothiazine derivative with analgesic Although tranquillity plays a substantial part in properties. Journal of the American Medical Association, curing pain the results described suggest to us that 178, 887. LASCELLES, R.G. (1966) Atypical facial pain and depression. the phenothiazines, antidepressants and antihist- British Journal of Psychiatry, 112, 651. may have an analgesic action which is in LASSMAN, P.L., MOODY, J.F. & GRYSPEERDT, G.L. (1959) part independent of their mood-altering effects. It Central pain due to cerebral ischaemia. Folia psychiatrica, is reasonable to suppose that this action is on the neurologica et neurochirurgica Neerlandica, 62, 34. it called by MERSKEY, H. (1965) The characteristics of persistent pain in multi-synaptic small-cell system, as is psychiatric illness. Journal of Psychological Research, 9 Noordenbos (1959). In other words the effect is 291. probably on the reticular activating system and on MERSKEY, H. & SPEAR, F.G. (1967) Pain: Psychological and related cell systems which are relatively slow-conduct- Psychiatric Aspects. Bailliere Tindall and Cassell; London. not to deny the intimate relationship be- MONTILLA, E., FREDERIK, W.S. & CASS, L.J. (1963) Anal- ing. This is gesic effect of methotrimeprazine and morphine: A tween pain and mood, but rather to suggest that they clinical comparison. Archives of Internal , 111, are affected by closely-related neuronal systems 725. which, although not identical, can each respond to NOORDENBOS, W. (1959) Pain. Elsevier, London. of pharmacological agent. PANACCIO, V. (1959) Trimeprazine: A new phenothiazine the same types derivative for treatment of pruritic dermatoses. Canadian Medical Association Journal, 80, 885. Acknowledgment PARADIS, B. (1962) Analgesic and anaesthetic properties of

H.M. wishes to thank the Chartered Society of Queen levomepromazine (Nozinan) (7044R.P.). Canadian Anaes-by copyright. Square for support. thetists Society Journal, 9, 153. ROSNER, S. (1957) The potentiating effect ofdiphenhydramine References hydrochloride (Benadryl). Journal of Nervous and Mental Disease, 125, 229. DE ALARCON, R. & CARNEY, W.M.P. (1969) Severe depressive mood change following slow-release intramuscular flu- SAUNDERS, C. (1963) The treatment of intractable pain in phenazine injection. British Medical Journal, 3, 564. terminal cancer. Proceedings of the Royal Society of Medi- BRADLEY, W.H. (1971) (Ed.) Proceedings of a Symposium on cine, 56, 195. Pain in Disablement. National Fund for Research into SAUNDERS, C. & WINNER, A. (1971) Analgesics in terminal Crippling Diseases, London. disease. British Medical Journal, 3, 245. BLOOMFIELD, S., SIMARD-SAVOIE, S., BERNIER, J. & TET- SIGWALD, J., BOUTTIER, D. & CAILLE, F. (1959) The treat- REAULT, L. (1964) Comparative analgesic activity of ment of herpes and post-herpetic pain. Study of the results levomepromazine and morphine in patients with chronic obtained with levomepromazine. Therapie, 14, 818. pain. Canadian Medical Association Journal, 90, 1156. SIGWALD, J. HEBERT, H. & QUETIN, A. (1957) The treatment http://pmj.bmj.com/ CASSINARI, V. & PAGNI, C.A. (1969) Central Pain: A Neuro- of herpes and post-herpetic pain (and other resistant forms surgical Survey. Harvard University Press, Cambridge, of pain) with phenothiazine derivatives. Semaine des Mass. hopitaux de Paris, 33, 1137. CHAVANNE, J. (1960) Treatment of pain with a group of VITALI, A. (1971) In: Proceedings of a Symposium on Pain in phenothiazine amines. Presse Medicale, 68, 2347. Disablement, pp. 32-3. National Fund for Research in EGBERT, L.D., BATTIT, S.E., WELCH, C.E. & BARTLETT, M.K. Crippling Diseases, London. (1964) Reduction of post-operative pain by encouragement WINNER, A. (1971) In: Proceedings of a Symposium on Pain and instruction of patients: A study of doctor-patient in Disablement. National Fund for Research in Crippling rapport. New England Journal of Medicine, 270, 825. Diseases, London. on October 2, 2021 by guest. Protected